The recent localization by Gusella et al. of the Huntington's disease (HD) gene to chromosome 4 (CH4) presents a breakthrough towards determining the genetic defect. It is now possible to develop reliable markers for carrier detection and to narrow the search for the involved gene. However, it will also be necessary to ascertain if heterogeneity exists in HD to assure reliability of any proposed clinically applied carrier detection programs and in identification of the genetic locus or loci, if more than one exists. This project will focus on two goals: (1) development of additional RFLP markers on CH4 linked to HD (including flanking markers) to be used in carrier detection and directing chromosome analysis towards the HD gene, and (2) evaluation of the possible existence of genetic heterogeneity in HD. Three approaches will be used: (1) We will develop regional HD family participation for DNA linkage studies. The resources listed in the Appendices will ensure the use of large multigenerational pedigrees in the study. As a clinically trained neurologist, the applicant will be able to reliably identify affected individuals in the pedigrees under study; the examinations will also be of benefit for evaluation of clinical variability if heterogeneity is discovered. (2) DNA studies will be done on EBV lymphoblast lines developed from members of the HD families in this project. A sorted CH4 library will be available for the efficient generation of RFLPs from this chromosome. A CH4 genomic library will be useful for creating haplotypes and for eventual chromosome "walking" studies. (3) Linkage studies will be directed towards both the confirmation in our families of linkage using the CH4 RFLPs discovered by Gusella et al. as well as linkage of new RFLPs generated in our laboratory. The use of large, multigenerational HD pedigrees as well as other large pedigrees available in our laboratory, with the generation of CH4 RFLPs, will allow for development of a general linkage map of CH4. This will enable investigators to link other genetic disorders to this chromosome. Specifically, we will be able to further investigate a recently reported link between peripheral neurofibromatosis [(NF) von Recklinghausen's Disease] and CH4 by utilizing NF patients already ascertained and sampled by our laboratory.